mRNA: Its past, present and future

January 2022

BY

Lance MinorPrincipal, Life Sciences National Co-Leader

Eskander YavarManufacturing National Practice Leader

Lessons from the COVID-19 mRNA vaccine research, development and manufacturing process

When the pandemic first hit in 2020, the world immediately began asking how long it would take to produce and distribute a viable vaccine. By most accounts, the timeline was faster than expected. It was even more impressive in an environment where supply chains were snarled by delays and facility shutdowns.  
 
Going into the pandemic, life sciences organizations were relying on just-in-time manufacturing, which meant they had little to no inventory cushion when supply chains stuttered. Additionally, there was a lack of geographic diversification in suppliers, meaning that lockdowns in one area of the world led to outsized supply chain disruptions, further compounding logistics issues.
 
At the same time, finding the necessary labor to fill trucking and shipping roles was an added challenge. Vaccine manufacturers also faced industry-specific regulations, including requirements for local manufacturing, sight approvals, safety and consistency. The EU also has requirements for production facilities to limit carbon emissions, which present additional challenges to companies operating in Europe.
 
Once the pandemic hit, things only got more complicated. Not only did the world need to develop, manufacture and distribute an effective vaccine at a speed and scale never before accomplished, but it needed to do so amidst facility shutdowns, labor shortages and an evolving shipping crisis.
 
Two of the effective vaccines that were developed looked different from any vaccine the world had used before. Pfizer and Moderna were the first to develop a market product using mRNA technology. Researchers had explored mRNA for years for its use as a treatment for cancer, HIV and other diseases, but once an effective vaccine was demonstrated, manufacturing facilities needed to transition from producing mRNA at the research scale, to producing it at the pandemic scale.
 

COVID-19 Vaccines – Materials and Supplies Needed to Transition from Research Scale to Pandemic Scale

Traditional vaccines inject a weakened form or component of a bacterial or viral pathogen,  which B Cells then absorb and produce antibodies against. mRNA provides the genetic code directly to dendritic cells where the ribosomes of the cells read the mRNA to produce COVID-19 proteins. This signals the standard immune pathways to produce protective antibodies.
 
For mRNA to be successfully delivered into the body, it requires a lipid nano particle (LNP) encapsulation, composed of four LNPs and a device to blend them. While three of those LNPs were easy enough to obtain off the shelf, the fourth, the ionic lipid, is customized. Each has a unique synthesis, is expensive to produce and there is limited global expertise to make it. And while a drug for a rare genetic disease using LNPs had already been on the market since 2018, COVID-19 presented the first time LNPs were used in medicine at a large scale. While there was concern that the ionic LNP would present a shortage, ultimately vast supply networks and the government’s use of the Defense Production Act were able to prevent a critical bottleneck.
 
But as one bottleneck opens, another tightens. Bioreactor bags were initially a solution to speed up vaccine production. They were cheaper and (initially) more readily available than large steel vats typically used to make most of the world’s vaccines. Bioreactor bags can be disposed after each use, speeding production time and minimizing the need to sterilize as many pieces of equipment after each batch. However, with large vaccine makers buying up these bags, and the makers of the bags slowing their production due to uncertainty around how many vaccine orders are needed, they are now in short supply. But with continued process improvement and research, the supply chain bottlenecks of today may one day be history.
 

What’s Next for mRNA and the Supply Chain and Production Outlook

There is now a wealth of research into mRNA treatments, gene editing and vaccines for diseases including cancer, HIV, influenza, Zika, genetic liver disease and much more. As mRNA technology continues to develop, we’re likely to see costs decrease and availability increase.
 
Researchers are now exploring ways to keep mRNA more stable and require less mRNA per effective dose. One potential method could be circular RNA. The theory is that by closing off strands of RNA in a loop, the stability of the mRNA would improve, allowing it to be effective in the body for longer periods of time and eliminating the need to “cap” the tails of the mRNA strands. Overall, this would reduce costs and could improve effectiveness and stability. Scientists are also exploring self-amplifying mRNA. With self-amplifying mRNA, the mRNA that is sent into cells would contain a replicating gene that would tell the body to make more mRNA, with each one telling the body to make multiple copies of the needed protein. This means that an effective dose could require even less mRNA, as the body is turned into its own mRNA factory.
 
In addition to advancements in biochemistry, we expect to see more advancements in production. Governments, biopharmaceuticals, manufacturers and shipping and logistics companies have already set up a vast production and distribution network of mRNA vaccines due to the needs of the COVID-19 pandemic. That means this network could be tapped if a surge in demand is needed. Not every biopharmaceutical company that researched a COVID-19 mRNA vaccine was successful in producing one. However, they have established additional production capacity. Future mRNA therapeutics and vaccines likely won’t require the same scale as COVID-19 vaccines, not only due to advancements in mRNA as discussed, but also because other diseases likely won’t require billions of doses.
 
We expect these advancements to continue to bring down the cost and improve the availability of mRNA vaccines and treatments. In fact, we’ve already seen progress when it comes to lowering the temperature for transportation and storage. Whereas Pfizer vaccines initially required ultra-cold transport, it has submitted stability data for FDA approval at 2-8 C for 31 days, equivalent to Moderna’s vaccine storage requirements. With continued process improvements and advancements in mRNA stability we expect future treatments to remain stable at refrigerator, or even room temperature, improving access and affordability.
 
mRNA represents an exciting innovation in medicine, and COVID-19 vaccines are just the beginning. With continued advancements in science, manufacturing processes and production capacity and networks, we’ll continue to see reduced cost and increased availability for this revolutionary technology across many infectious and non-infectious diseases.
 
For more information on mRNA, watch our recent webinar with the International Pharmaceutical Federation.
 
A version of this article appeared as the November issue for Global Value Chain Chronicle.